Guardian Protein Could Keep Alzheimer’s at Bay

Alzheimer’s disease robs 5.3 million older adults of their memories, their work, and their family and social lives. The theft might be occurring because a “watchman” in the human brain has fallen asleep on the job, says Dr. Benjamin Bobay, a senior research associate in the Department of Molecular and Structural Biochemistry. So he is studying this watchman, trying to determine if he is truly sleeping on duty and how to help him provide better protection for the brain.

“There are a lot of pathways that lead to cell death. Calbindin is unique in that it can control several at once.”

Bobay’s watchman is a protein known as calbindin D28K, a neuro-protective molecule designed to ensure that certain processes in the brain occur normally. Calbindin protects the brain in several ways, such as binding metal ions and regulating other proteins. One of those proteins, caspase-3, is involved in the formation of plaques and tangles of protein fibers in and around brain cells, which are two hallmarks of Alzheimer’s. Elevated concentrations of metal ions—about three to five times higher than normal—have also been found near the plaques, leading researchers to believe that is another characteristic of the disease.

A member of the team—led by William Neal Reynolds Distinguished Professor of Biochemistry John Cavanagh—that first discovered the structure of calbindin in 2006, Bobay now is studying how the protein carries out its various duties. He’s also looking at whether some functions impede others, which could possibly trigger the development of both plaques and tangles and the onset of Alzheimer’s. “There are many pathways that lead to cell death,” he says. “Calbindin is unique in that it can control several at once.”

Calbindin has six sites where it can bind metal ions, but only four are active. Bobay has found that, by adjusting a few amino acids, he can activate the other two sites without changing the structure of the molecule. Using nuclear magnetic resonance imaging, he is testing the protein with various metals—calcium, zinc, magnesium, copper, and iron—to determine if the structure changes as it binds different types of ions and whether it has an affinity for one metal over the others. Bobay also hopes to find out if any combination of attached ions helps or hinders calbindin’s ability to regulate caspase-3. He is working with researchers at the Mayo Clinic in Minnesota to test his findings in mice. “If we can find a way to slow the onset of Alzheimer’s,” he says, “this incurable and progressive disease won’t take such a toll on patients and their families.“

 

Dr. Benjamin Bobay inserts a sample of calbindin D28K molecules into a nuclear magnetic resonance (NMR)imager to study whether the structure of the protein changes as it binds to different metal ions. Calbindin’s binding sites are depicted as swirling, ribbon-like structures in the illustration below, while the spheres represent a peptide target from the caspase-3 protein.